Congestive heart failure (CHF) is a leading health burden for which there is an unmet need for understanding disease progression in order to develop therapeutic, diagnostic and preventative strategies. Increasing evidence has demonstrated that the kidney as well as the heart plays a central role in CHF. The objective of this highly translational application is to define mechanisms of an impaired link between the heart and kidney in the control of cardiorenal homeostasis in human and experimental CHF and to promote novel therapeutics and innovative diagnostics for cardiorenal protection. Our broad working hypothesis is that a defect in the GC/cGMP pathway which links the heart and kidney is a key mechanism of impaired renal and cardiac function in CHF. We also hypothesize that cardiorenal dysfunction can be overcome with innovative GC/cGMP-based therapeutics and that knowledge gained will also lead to novel diagnostics for CHF. Aim 1: Establish that proBNP is a circulating hormone secreted by the normal human heart that is processed to mature BNP in the circulation. Establish that the processing of circulating proBNP by corin is impaired in CHF. Aim 2: Establish that proBNP is the superior molecular form of BNP to serve as a biomarker for the detection of ventricular dysfunction and as a prognostic biomarker for adverse cardiovascular outcomes. Establish that the BNP genetic variant rs198389 affects circulating proBNP in the general community and that the optimal BNP-based biomarker strategy integrates measurement of proBNP with genotyping for rs198389. Aim 3: Establish that dual GC-A/GC-B activation with a Mayo designed chimeric NP (CD-NP) is superior to GC-A activation alone with BNP in improving cardiorenal function in humans with CHF and impaired renal function. Establish the comprehensive cGMP activating properties of dual GC-A/GC-B stimulation with CD-NP as compared to GC-A alone with BNP and GC-B alone with CNP in human renal glomerular cells. Finally, establish that CD-NP is highly resistant to protease degradation by human NEP secondary to the presence of the C-terminus of DNP. Aim 4: Establish that CHF progression can be delayed with chronic GC-A/GC-B activation with CD-NP compared to GC-A activation with BNP alone in a model of progressive CHF. PUBLIC HEALTH RELEVANCE: A family of hormones in the heart and kidney link these two organs that contribute to the optimal regulation of fluid volume and blood pressure. In response to stress to the heart these hormones function to preserve heart and kidney function but when heart failure is severe this system may be defective. Our proposal seeks to better understand this hormonal heart and kidney connection leading to novel new drugs and diagnostics for human heart failure.